Major depressive disorder is frequently characterized by periodic depressed mood and the loss of interest, often with thoughts of death. Severe forms of depression affect 2�C5% of the population worldwide, and up to 20% suffer from milder forms of the disease, and depression is also associated with high rates of relapse, recurrent, disability, and death. Despite the high morbidity and mortality associated with MDD, the etiology and pathophysiology of MDD have not been precisely defined. Family, twin, and adoption studies provide strong evidence for an important genetic component. To uncover the genetic mechanisms underlying Trihexyphenidyl HCl susceptibility to depression and related traits may also prove a successful way to understand better the etiological features of MDD. Stress response and neurotoxic effects are important etiological hypotheses about depression. Neurotoxins damage or kill hippocampal cells, leading to many depressive symptoms. A deficient function of neuroprotective peptides, for example, brain-derived neurotrophic factor, which reduces serum BDNF in MDD. Hypothalamic pituitary-adrenal axis dysregulation and reduced neuroplasticity in depression are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity. As a major mediator of the stress response in the central nervous system, corticotropin releasing hormone affects other central processes, such as learning and memory, synaptic plasticity, and neuroprotection. Abnormal CRH neurotransmission and receptor signal transduction has been proposed to be a critical mechanism for stress pathophysiology that leads to major depression. Bayatti considered that CRH regulates BDNF Citiolone expression through influencing cAMP and Ca2+ signaling pathways. Based on different neuroanatomical expression patterns, there are two primary receptors subtypes in the central nervous system CRHR1 and CRHR2. CRH has a higher affinity for CRHR1 than for CRHR2, and in the brain, CRHR1 is expressed at high levels in the hippocampus, cortex and cerebellum. CRH binding to CRHR1 typically activates adenylate cyclase, which leads to increased intracellular concentrations of cAMP and activation of protein kinase A. One putative target is the BDNF, whose expression is controlled by cAMP-elevating agents in neurons. In addition to its role as a classical target-derived growth factor during neuronal development, BDNF is an essential autocrine factor, released and acting locally after neuronal depolarization. As CRHR1 may play a significant role in the etiology and treatment of depression, it is suggested that CRHR1 is a relevant candidate gene for MDD. In Mexican-Americans population, a significant association has been reported between CRHR1 and a greater response to selective serotonin reuptake inhibitors treatment in highly anxious MDD patients, but the distribution of the MDD was similar to the healthy controls.